A high-fat, low-carbohydrate (ketogenic) diet is an effective treatment for pediatric epilepsy. Though clinical use of this diet is well established and growing, its mechanism(s) of action remain putative, and, more importantly, cognitive effects of this diet are poorly understood. Published hypotheses suggest that clinical effects of a ketogenic diet stem from increased brain mitochondrial bioenergetics and/or inhibitory neurotransmitters or neuromodulators, including GABA and adenosine. Enhanced central inhibition would be predicted to influence normal synaptic plasticity and alter cognitive/behavioral outcomes, and the magnitude of diet-induced synaptic and bioenergetic changes may differ with age. In both juvenile and adult rats, we propose to quantify mitochondrial function in a variety of brain areas and determine the regional selectivity of ketogenic diet-related bioenergetic changes (Specific Aim 1), and to investigate synaptic transmission in one selected brain region (the hippocampus) in awake freely-moving rats and determine if synaptic plasticity is affected by the diet (Specific Aim 2). Our hypothesis is that the ketogenic diet will cause regional changes in mitochondrial function in brain areas critical for seizures, and will decrease the magnitude of synaptic plasticity measured in the in vivo hippocampus. Our Preliminary Data support our hypothesis by showing strikingly diminished hippocampal long-term potentiation in rats maintained on the ketogenic diet for three weeks. This proposal is an interdisciplinary collaboration among the Neuroscience Program and the Departments of Engineering and Psychology, and it promotes mutually beneficial interactions between laboratories with electrophysiological and biochemical expertise. The feasibility of these proposed experiments is extremely high: The standard biochemical methodology is demonstrated in our preliminary studies and well-characterized in the literature. The in vivo electrophysiological methodology has been used extensively in our laboratory in multiple species and size ranges, leading to a number of publications over the last decade. The undergraduate participation and training is clear, as trained, supervised students are involved in all steps of all proposed experiments. The clinical relevance includes a better understanding of the regional brain responses to a ketone-based metabolism, and a much-needed characterization of the influence of a current therapy for pediatric epilepsy on hippocampal synaptic plasticity. PUBLIC HEALTH RELEVANCE: The ketogenic diet is a high fat/very-low carbohydrate diet used successfully to treat pediatric epilepsy. Despite its use in children, little is known about how diet therapy affects brain energy, learning or memory. Based on published and preliminary work, we hypothesize that brain energy and activity will change in areas of the brain affected by seizures. Using an animal model (rat) we will test the effects of ketogenic diet therapy on brain energy and on the biological mechanisms that are important for learning and memory.